The proposed work is a continuation of a MERIT Award and involves the use of computer based design chemical synthesis, mechanistic biochemistry and chemical biology to design, synthesize and evaluate new compounds with novel structures , unique or novel modes of action, and clinical potential for the treatment of lymphoma, resistant cancer, cognitive dysfunction (e.g., Alzheimer's disease) and HIV/AIDS. Four projects are involved: bryostatin and bryologs, apoptolidins, new kinase inhibitor scaffolds for chemical genomics and molecular transporters for drug and probe delivery. Bryostatin is currently in clinical trials for cancer and Alzheimer's disease. Its supply is extremely limited and its clinical performance is non-optimal. New designed analogs are proposed that would address the supply problem and be tunable and potentially clinically superior as chemotherapeutic agents for the treatment of lymphoma and more generally cancer. Apoptolidin is among the most selective compounds in the NCI 60 cell line screen. New apoptolidins have been identified in our lab. Derivatives will be prepared to determine the basis for apoptolidin's exceptional selectivity and the activities of the new agents. Novel catalyst screening methodology will be used to exert reagent control over derivatization reactions. Ongoing studies on the mode of action of apoptolidins will be conducted. The design, synthesis, and evaluation of new scaffolds for kinase inhibition will be conducted with an emphasis on step economical access to novel, potent, and selective agents that could serve as leads for the development of new therapies. The scaffold design draws inspiration from therapeutic leads now in clinical trials. Molecular transporters, agents that enable or enhance cellular entry of molecules that by themselves would not enter cells or do so poorly, will be studied with an emphasis on their mode of cellular entry, selectivity and therapeutic value. A new strategy involving the use of transporters to overcome resistant cancer will be advanced and new drug conjugates prepared and evaluated to determine its generality. Studies on activatable transporters for targeted therapy are proposed. Studies on the use of transporters for adult stem and progenitor cell uptake will be conducted. Collectively this program is designed to advance science with an emphasis on creating new therapeutic opportunities.